The present invention concerns heterocyclic carbon compounds comprising 4-phenyl-1,4-dihydropyridines with a nitrogen heterocycle-containing moiety attached to the 3-position of the 4-phenyl ring. These compounds act as NPY antagonists.
A substantial body of art has accumulated over the past two decades with respect to 4-aryl-1,4-dihydropyridine compounds. A large number of these possess calcium antagonist properties and find utility in the treatment of cardiovascular diseases. Several 4-aryl-1,4-dihydropyridines with piperidine-ring-containing-substituents have been reported.
A series of compounds of formula (1) was claimed to be ##STR2## useful as vasodilators, antihypertensives and diuretics in U.S. Pat. No. 4,707,486.
A series of dihydropyridines, including compounds of formula (2), were disclosed and claimed to have antitumor promoting ##STR3## activity in European Patent Application 533,504.
European Patent Application 534,520 discloses related compounds having formula (3) wherein R.sup.5 is alkyl, phenyl and aralkyl, ##STR4##
A compound of formula (4) has been disclosed in JO 4049-237-A and claimed to be an inhibitor of Phospholipase A.sub.2. ##STR5##
Of less significance is a series of antihypertensive dihydropyridine anilide derivatives disclosed in U.S. Pat. No. 4,829,076 and containing compounds of formula (5) ##STR6## in which B is a chemical bond or an alkylene group.
These reference compounds are readily distinguished structurally from the compounds of the instant invention by virtue of many of the art compounds having only simple piperidine substituents attached to the dihydropyridine ring itself as well as by the nature of most of the linking functional groups, e.g. oxyalkylenyl and carboxylate groups. In contrast, compounds of the instant invention contain ring-fused or spiro-ring nitrogen heterocycles in a moiety attached to the 3-position of the 4-phenyl ring by means of an anilide or urea connection. Not only are the present compounds structurally novel, they also have been discovered to possess novel NPY antagonist activity while having greatly reduced calcium antagonist properties.
In summary, the prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel dihydropyridine derivatives having good antagonist activity at NPY Y.sub.1 receptor sites and reduced effects on other systems.
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 from porcine brain..sup.1,2 The peptide is a member of a larger peptide family which also includes peptide YY (PYY), pancreatic peptide (PP), and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y is very highly conserved in a variety of animal, reptile and fish species. It is found in many central and peripheral sympathetic neurons and is the most abundant peptide observed in the mammalian brain. In the brain, NPY is found most abundantly in limbic regions. The peptide has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and the regulation of coronary tone.
Structure-activity studies with a variety of peptide analogs (fragments, alanine replacements, point mutations, and internal deletion/cyclized derivatives) suggest a number of receptor subtypes exist for NPY..sup.2b These currently include the Y.sub.1, Y.sub.2, Y.sub.3, and the Y.sub.1-like or Y.sub.4 subtypes.
Although specific peptidic antagonists have been identified for most of the subtypes, few selective non-peptidic antagonists (see Charts 1 and 2) have been reported to date. Several competitive but nonselective, non-peptidic antagonists are known, however (Chart 1). The heterocyclic guanidine derivative He 90481 (4) was found to be a weak but competitive antagonist of NPY-induced Ca.sup.++ entry in HEL cells (pA.sub.2 =4.43)..sup.3 The compound was also found to have .alpha..sub.2 -adrenergic and histaminergic activity at this dose range. D-Myo-inositol-1,2,6-triphosphate (5) was reported to be a potent but non-competitive antagonist to NPY-induced contractions in guinea pig basilar artery..sup.4 Similarly, the benextramine-like bisguanidines 6a and 6b were reported to displace .sup.3 H-NPY in rat brain (IC.sub.50, 19 and 18.4 .mu.M) and to display functional antagonism in rat femoral artery..sup.5 The bisguanidine 6b was shown to be functionally selective for the Y.sub.2 receptor since it antagonized the effect of the NPY.sub.2 agonist NPY.sub.13-36 but had no effect on the vasoconstrictive activity of the NPY.sub.1 agonist [Leu.sup.31, Pro.sup.34 ]NPY..sup.5c
Compound (6), shown in Chart 2 and known as BIBP 3226.sup.6, displaces I-125 Bolton-Hunter labeled NPY in human neuroblastoma cells (SK-N-MC). Compound (6) antagonized the NPY-induced increase in intracellular Ca.sup.++ in SK-N-Mc cells as well as antagonizing the NPY-induced pressor response in pithed rat experiments.
In addition to displacing I-125 labeled NPY and PYY in human neuroblastoma cells, compound (7), SR 120819A.sup.7, also antagonized NPY-related increases in diastolic blood pressure in an anesthetized guinea pig model.
In sum, the compounds of this invention may be distinguished over compounds of the prior art on the basis of molecular structure and biologic activity. There is nothing in the prior art that anticipates or suggests the novel NPY antagonists of the present invention.